The present invention generally relates to a system for enhancing and improving the transcutaneous or transdermal delivery of various topical chemicals or drugs (also referred to herein as xe2x80x9cactive agentsxe2x80x9d).
Heretofore, ultrasound has been primarily used for diagnostic purposes with an outstanding safety record. It has also been used for dental care. Physical therapy uses ultrasound primarily to generate deep heat and also sometimes as an adjunct to wound healing. Some attempts have been made since the 1950""s to use ultrasound to deliver hydrocortisone into joint spaces (originally for bursitis) or lidocaine (for pain relief) rather than injecting with needles. The current use of ultrasound to deliver drugs is primarily its use in physical therapy for non-invasive treatment of certain musculoskeletal disorders. Research in recent years has dramatically increased the understanding of ultrasound and its effects on skin and transport of topical agents. However, there is no consensus on how to optimally increase the flux or flow of topical agents across the skin using ultrasound.
Although ultrasound has been useful to deliver drugs very deeply into joints, several problems exist with this technique. For example, if high frequency ultrasound is directed toward a bone for an extended period of time, then the energy can cause a burn. To some extent a focused beam tends to cause uneven concentration and uneven penetration, and may also cause injuries. This is particularly true with older ultrasound equipment, but is also true of many current ultrasound technology in clinical use today. An additional problem with some earlier ultrasound equipment is that a two to four hour exposure period may be required. The newer ultrasounds use frequencies that provide results in a five to twenty minute time frame.
The use of ultrasound to deliver agents transcutaneously is generally termed xe2x80x9csonophoresisxe2x80x9d but occasionally is termed xe2x80x9cphonophoresisxe2x80x9d. Ultrasound generally comprises high-frequency sound waves that are above the human hearing range (usually greater than 20,000 Hertz (Hz) frequency units).
The sound waves may be generated by applying an alternating high frequency electrical current to a crystal such as a quartz, silicone dioxide, lithium sulfate of barium titanate. This current distorts the crystal, creating high frequency vibrations known as the piezoelectric effect. The sound waves produced have energy and may penetrate matter, depending on its acoustic density and composition. These sound waves may be delivered either in a focused manner and concentrated to a focal point (similar to the effects achieved with a magnifying lens and sunlight) or delivered in a non focused manner, termed xe2x80x9ccollimated,xe2x80x9d whereby the beam is uniform and parallel with no focal point (similar to falling rain).
The depth of penetration of ultrasound is inversely related to the frequency. Current diagnostic and therapeutic ultrasound typically ranges in frequency from 1-3 MHZ to 4-10 MHZ. Delivery may be pulsed in bursts or continuous beam modes, either stationary or continuously moving (usually at a rate of about one inch per second). The energies used generally range from a few milliwatts to a few watts.
The ultrasound energy is usually delivered through a transducer head. When used on skin, it is usually placed in direct contact with the skin using a coupling medium (which is often an aqueous gel), as shown, for example, in FIG. 1.
It is also known that topical agents may be applied directly to the skin. Sometimes absorption of these agents may be enhanced by techniques such as occlusion with synthetic materials (e.g. plastic), or transport may be enhanced by using low level electrical means such as galvanic current application or the technique of ionophoresis.
One problem with this known methodology is that of achieving more effective beneficial therapeutic clinical effects with topical agents by reaching higher concentrations in the dermis without damaging the dermis and/or the epidermis. Such damage may include undesirable and intolerable side effects such as flaking, peeling, persistent redness or burning.
The problem has not been adequately solved by simply using topical agents in various vehicles at higher strength. Using solutions at higher strength may tend to magnify the side effects. Using solutions at higher strength may also worsen internal systemic side effects. Simply using solutions at higher strength tends to work too broadly, and generally fails to selectively cause the desired effect.
Ionophoresis tends to work only if the molecules can be broken up into positive and negative ions and then driven in. A primary disadvantage of this technique is that many drugs cannot be broken up into positive and negative ions. Another disadvantage is that many drugs lose their effectiveness if broken up in this manner.
It has been proposed that drugs may be injected into the skin using a hypodermic needle. However, a primary disadvantage of this technique is that it generally fails to deliver the drug uniformly.
It has been proposed that drugs may be taken orally. However, in many cases this technique is not practical. For example, oral ingestion of vitamin C generally fails to provide a sufficiently high concentration of the drug in the skin. The technique may also involve certain risks. For example, oral ingestion of vitamin A derivatives may cause liver damage or birth defects.
It can be seen, therefore, that while the drugs themselves may be quite effective if used selectively, each of the traditional routes has one or more inherent limiting factors which prevent or inhibit the drugs from achieving their maximum effectiveness.
In accordance with the present invention, these and other objectives may be achieved by providing an optimal selection of ultrasound parameters such as frequency, intensity, pulse length, beam characteristics and application time on the skin (including both human and animal) to enhance the transport of topical agents into epidermal, dermal and subcutaneous tissues. The present invention may be useful to produce higher concentrations of such an agent than may be accomplished by current topical application or delivery methods. Such increased concentrations may have beneficial effects depending on the characteristics of the topical agent delivered. Patients who cannot tolerate current topical application methods may achieve beneficial effects by delivering similar concentrations of the agent with little or no side effects. Topical agents which cannot normally penetrate the skin with current methods may be transported into the dermis
The effects of ultrasound on skin result from the release of energy. These include the non-hermal effects of (1) cavitation, (2) mechanical stress as well as (3) thermal effects.
It appears that ultrasound exposure in the therapeutic range causes cavitation in the keratinocytes of the stratum corneum as the primary effect in increasing skin permeability for transcutaneous transport of topical agents (cavitation is a process where bubbles are formed which oscillate causing structural disorder of the intercellular lipid bilayers of the keratinocytes).
In effect, this process is somewhat analogous to loosening the xe2x80x9cmortar between the bricksxe2x80x9d and expanding the xe2x80x9cspaces between these bricksxe2x80x9d so that the topical agent has a transport pathway to reach the epidermis and the deeper dermis of the skin. Drug molecules that are too large to penetrate the skin at all when applied topically may achieve significant penetration when used in conjunction with sonophoresis with proper parameters. See FIGS. 3 and 4.